Ester acid-catalyzed hydrolysis

Ester hydrolysis is the most studied and best understood of all nucleophilic acyl substitutions. Esters are fairly stable in neutral aqueous media but are cleaved when heated with water in the presence of strong acids or bases. The hydrolysis of esters in dilute aqueous acid is the reverse of the Fischer esterification (Sections 15.8 and 18.14)  

When esterification is the objective, water is removed from the reaction mixture to encourage ester formation. When ester hydrolysis is the objective, the reaction is carried out in the presence of a generous excess of water. Both reactions illustrate the application of Le Chatelier s principle (Section 6.10) to organic synthesis. 

The compound having the structure shown was heated with dilute sulfuric acid to give a product having the molecular formula C5H12O3 in 63-71% yield. Propose a reasonable structure for this product. What other organic compound is formed in this reaction  

The pathway for acid-catalyzed ester hydrolysis is given in Mechanism 19.3. It is precisely the reverse of the mechanism given for acid-catalyzed ester formation in Section 18.14. Like other nucleophilic acyl substitutions, it proceeds in two stages. A tetrahedral intermediate is formed in the first stage, and this tetrahedral intermediate dissociates to products in the second stage. 

A key feature of the first stage (steps 1-3) is the site at which the starting ester is protonated. Protonation of the carbonyl oxygen, as shown in step 1 of Mechanism 19.3, gives a cation that is stabilized by electron delocalization. The alternative site of protonation, the alkoxy oxygen, gives rise to a much less stable cation. 

Conversion of Esters to Other Carboxylic Acid Derivatives 

Reaction with ammonia and amines (Section 20.13) Esters react with ammonia and amines to form amides. Methyl and ethyl esters are the most reactive. 

Hydrolysis (Sections 20.9 and 20.10) Ester hydrolysis may be catalyzed either by acids or by bases. Acid-catalyzed hydrolysis is an equilibrium-controlled process, the reverse of the Fischer esterification. Hydrolysis in base is irreversible and is the method usually chosen for preparative purposes. 

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FIGURE 20 4 The mecha nism of acid catalyzed ester hydrolysis Steps 1 through 3 show the formation of the tetrahedral intermediate Dissociation of the tetrahe dral intermediate is shown in steps 4 through 6... 

On the basis of the general mechanism for acid catalyzed ester hydrolysis shown in Figure 20 4 write an analogous sequence of steps for the spe cific case of ethyl benzoate hydrolysis... 

Kinetic Considerations. Extensive kinetic and mechanistic studies have been made on the esterification of carboxyHc acids since Berthelot and Saint-GiHes first studied the esterification of acetic acid (18). Although ester hydrolysis is catalyzed by both hydrogen and hydroxide ions (19,20), a base-catalyzed esterification is not known. A number of mechanisms for acid- and base-catalyzed esterification have been proposed (4). One possible mechanism for the bimolecular acid-catalyzed ester hydrolysis and esterification is shown in equation 2 (6). 

Although the previous two sections of this chapter emphasized hydrolytic processes, two mechanisms that led to O- or N-acylation were considered. In the discussion of acid-catalyzed ester hydrolysis, it was pointed out that this reaction is reversible (p. 475). Thus, it is possible to acylate alcohols by reaction with a carboxyhc acid. To drive the reaction forward, the alcohol is usually used in large excess, and it may also be necessary to remove water as it is formed. This can be done by azeotropic distillation in some cases. 

A system of this type is commonly said to possess a fast preequilibrium step. Proton transfers constitute a veiy important class of fast preequilibria, as illustrated by Scheme XVII for acid-catalyzed ester hydrolysis. 

Specific acid catalysis is catalysis by the hydronium ion (in water) or the lyonium ion in general. Acid-catalyzed ester hydrolysis is an example. 

Thomson1 < vv Click Organic Process to view an animation of the steps involved in acid-catalyzed ester hydrolysis. 

Acid-catalyzed ester hydrolysis can occur by more than one mechanism, depending on the structure of the ester. The usual pathway, however, is just the reverse of a Fischer esterification reaction (Section 21.3). The ester is first activated toward nucleophilic attack by protonation of the carboxyl oxygen atom, and nucleophilic addition of water then occurs. Transfer of a proton and elimination of alcohol yields the carboxylic acid (Figure 21.8). Because this hydrolysis reaction is the reverse of a Fischer esterification reaction, Figure 21.8 is the reverse of Figure 21.4. 

Active Figure 21.8 MECHANISM Mechanism of acid-catalyzed ester hydrolysis. The forward reaction is a hydrolysis the back-reaction is a Fischer esterification and is thus the reverse of Figure 21.4. Sign in afwww.thomsonedu.com to see a simulation based on this figure and to take a short quiz. 

The acid-catalyzed ester hydrolysis provides a good target for MM treatments. DeTar first used hydrocarbon models in which an ester was approximated by an isoalkane (74) and the intermediate (75) by a neoalkane (76). He assumed that if the rate of reaction truly is not influenced by polar effects but is governed only by steric effects of R, as has been generally postulated, the rate must be proportional to the energy difference (AAH ) between 74 and 76. The AAH f is mainly determined by the van der Waals strain in these branched alkanes. Nonsteric group increment terms were carefully adjusted, and statistical mechanical corrections for conformer populations... 

Acid-Catalyzed Hydrolysis. In acid-catalyzed ester hydrolysis the species that undergoes the rate-determining step is the protonated ester (Fig. 13.10). When the molecule is in this protonated form, the enhanced depletion of electrons near the central carbon promotes the approach of an electron-rich oxygen of a water molecule. Hence, the hydrolysis rate depends on the fraction of compound molecules that are protonated. This fraction, in turn, depends on how strong a base the ester function is. If we define an acidity constant (see Chapter 8) for the protonated species... 

RATE COEFFICIENTS FOR ACID-CATALYZED ESTER HYDROLYSIS AT 25°Ca... 

The acid-catalyzed hydrolysis of orthoesters is very much faster than that of esters. The second-order rate coefficient for the hydrolysis of ethyl acetate is of the order of 10"4 1-mole-1-sec1 at 25°C, whereas that for the hydrolysis of ethyl orthoacetate103 is of the order of 104 l-mole-1-sec 1, and that for the breakdown of a monoalkyl orthoester must be faster still. If the breakdown of the tetrahedral intermediate is partially rate-determining in acid-catalyzed ester hydrolysis, therefore, its concentration must be very small that is, the equilibrium for its formation must be highly unfavourable. This... 

Scheme 1. Mechanism (Aac2) for acid-catalyzed ester hydrolysis.

It has been recognized for many years that acid-catalyzed ester hydrolysis... 

This would have both a solvent effect and a mass law effect on the rate of ester formation. The error is systematic, since it is most serious for the slower ester formation reactions, and consequently the p value calculated by Jaffe144 from the data of Hartman and Borders142 is not accurate. Later workers allowed for this side-reaction 46 or used aromatic sulphonic acids rather than HC1 as the catalyst145147. However, whatever the exact p values, it is quite clear that the polar effects of substituents on acid-catalyzed ester hydrolysis and formation are small. 

The ortho substituent constants, s°, on the other hand, gave no significant correlation with van der Waal s radii. The effects of groups in the ortho position are fully accounted for in terms of o-, and steric effects of groups in the ortho position are constant, negligible, or non-existent251. This result was confirmed by an analysis of the data for acid-catalyzed ester hydrolysis and formation, including those of Tables 20 and 22. 

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